The eye, particularly the conjunctiva, has a relatively large number of mast cells. When allergens are present they can bind to immunoglobulins on the surface of these mast cells and trigger their degranulation (breakdown). Degranulation releases mast cell components, including histamine, into the environment outside the mast cell. Through a variety of mechanisms these components produce ocular surface inflammation resulting in itching, tearing, lid and conjunctival edema/redness, and photophobia. This is frequently designated as an acute phase response, as is seen with seasonal allergic conjunctivitis and perennial allergic conjunctivitis. Topical ocular application of histamine receptor antagonists such as olopatidine or mast cell stabilizers such as lodoxamide are frequently used to alleviate these symptoms [for a review, see: Bielory et al., Drugs 2005, 65(2), 215-228].
As is the case in other allergic diseases, the acute phase response can progress to a late phase response characterized by an influx of eosinophils and neutrophils into the conjunctiva. In the associated chronic allergic disease, exemplified by vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis, eyelid swelling and remodeling of the ocular surface tissues can occur. In severe cases the patient experiences extreme discomfort and sustains damage to the ocular surface. For such instances there is no highly effective and safe treatment regimen. Although topical administration of corticosteroids is effective in severe cases, chronic use is contraindicated due to an increased risk for the development of cataracts and glaucoma [for a review, see: Ono and Abelson, J. Allergy Clin. Immunol. 2005, 115(1), 118-122].
Lipoxin A4 is an anti-inflammatory eicosanoid biosynthesized from arachidonic acid, and is produced locally at inflammation sites via the interaction of neutrophils with platelets or of other leukocytes with epithelial cells. Lipoxin A4 is believed to act endogenously to resolve inflammation by inducing apoptosis and phagocytosis/clearance of activated leukocytes. Lipoxin A4 binds to at least two receptors with nM affinity. The first is the lipoxin A4 cognate receptor, called ALXR. This is the same as the formyl peptide receptor FPRL-1. The second receptor is that for the cysteinyl leukotriene LTD4. Lipoxins are thought to function as ALXR agonists and LTD4 receptor antagonists [Fronert et al., Am. J. Pathol. 2001, 158(1), 3-8].

Several researchers have reported that administration of lipoxin A4 structural analogs inhibit allergen-induced eosinophil infiltration, decrease production of pro-inflammatory allergic mediators like cysteinyl leukotrienes, IL-5, and eotaxin, and reduce tissue edema in several animal models, including: a mouse model of allergic asthma [Levy et al., Nat. Med. 2002, 8(9), 1018-1023]; allergen-induced skin inflammation in mice and guinea pigs [Schottelieus et al., J. Immun. 2002, 169, 7063-7070]; and allergen-induced pleurisy in rats [Bandeira-Melo et al., J. Immun. 2000, 164(5), 2267-2271].
Lee et al. have disclosed that compounds 1 and 2 inhibit LTB4-induced chemotaxis of neutrophils as potently as lipoxin A4 [Lee et al., Biochemical and Biophysical Research Communications 1991, 180(3), 1416-21]. As the authors' stated purpose was to investigate the relationship between this bioassay readout and the structure of lipoxin A4 analogs that they synthesized, one conclusion could be that compounds 1, 2, and lipoxin A4 inhibit LTB4-induced neutrophil chemotaxis by the same mechanism, namely activation of the ALXR.

However, this theory may well be invalid. An essential experiment to test this theory would be to ascertain whether the chemotaxis inhibition effect for these three compounds could be blocked by a selective ALXR antibody or small molecule antagonist. This was not performed, since at the time of Lee et al.'s disclosure neither the ALXR protein nor its associated mRNA had been sequenced [this was accomplished in 1994: J. Exp. Med. 1994, 180(1), 253-260]. An explanation for the neutrophil chemotaxis inhibition displayed by 1, 2, and lipoxin A4 which is equally consistent with this disclosure would be that 1 and 2 act via leukotriene B4 receptor antagonism while lipoxin A4 acts via ALXR agonism and/or perhaps antagonism at the leukotriene D4 (LTD4) receptor [Gronert et al., Am. J. Path. 2000, 158(1), 3-9]. Furthermore it is known that the biological activity of lipoxin A4 is critically dependent on the presence of a hydroxyl at position 15; oxidation to the carbonyl [Petasis et al., Prostaglandins Leukot. Essent Fatty Acids 2005, 73(3-4), 301-321] or replacement with a hydrogen [Jozsef et al., Proc. Natl. Acad. Sci. USA 2002, 99(20), 13266-13271] greatly diminishes biological activity. However 1 and 2 lack this hydroxyl, indeed they lack any atoms at all beyond the primary hydroxyl group of their triol array. To the best of our knowledge there have been no subsequent reports on the biological activities of either 1 or 2. Thus absent receptor-linked functional data, one skilled in the art could reasonably doubt that these compounds' inhibition of LTB4-induced neutrophil chemotaxis is due to ALXR agonism.